Natural-derived acetophenones: chemistry and pharmacological activities

Acetophenones are naturally occurring phenolic compounds which have found in over 24 plant families and also fungi strains. They are exist in both free or glycosides form in nature. The biological activities of these compounds have been assayed and reported including cytotoxicity, antimicrobial, antimalarial, antioxidant and antityrosinase activities. Herein, we review the chemistry and biological activity of natural acetophenone derivatives that have been isolated and identified until January 2024. Taken together, it was reported 252 acetophenone derivatives in which the genera Melicope (69) and Acronychia (44) were the principal species as producers of acetophenones. Graphical Abstract


Introduction
Acetophenones, as a group of phenolic compounds, produced by many plants of various families for some reasons such as repelling insects [1].The proven ability of acetophenone-rich plants to fend off pests and insects has shed light on the perspective of using acetophenone derivatives as pesticides.With the crops suffering catastrophic losses due to pest attacks and diseases, and the public opinion bending towards mitigating the use of chemical pesticides, acetophenone rises as a candidate for an eco-friendly alternative for synthetic pesticides [2].Plant-derived acetophenones, also, are important precursors for drug production.For example, acetophenone derivatives such as apocynin (207) and paeonol (217) show anti-inflammatory traits without any negative side effects, which make them perfect option for synthesizing drugs.The use of plants containing paeonol in folk medicine for their therapeutic properties dates back to a millennia ago [3].Acetophenones can also contribute more to therapeutic applications due to their other biological activities such as anticancer, analgesic, antioxidant, cardioprotective, neuroprotective, and antidiabetic [4].In addition to their biological applications, acetophenone derivatives are used in the food and fragrance industries, primarily for their orange blossom flavor [5].They are also used as fragrance ingredients in detergents, soaps, and perfumes.In addition, acetophenones and their derivatives also have a variety of applications in the cosmetics production, especially in the making of odorless and colorless cosmetics with good antiseptic effects [6].They are also used in the production of sunscreen products to protect against UV radiation [7].Additionally, acetophenone compounds are employed in the production of alcohol, aldehydes, resins, esters, fragrances, and pharmaceuticals.They are important intermediates for the synthesis of natural products and marketed drugs, and they find wide use in fields such as biology, pesticides, polymers, and materials science.Moreover, they are ideal synthons for multicomponent reactions, including three-and fourcomponent reactions, due to their commercial availability and accessibility [8].Furthermore, highly functionalized acetophenone derivatives have interesting biological properties and are valuable compounds for supramolecular or medicinal chemistry [9].This article provides a review study over the various natural acetophenone compounds that have been extracted and analyzed plants and microbial populations until January 2024.

Search strategy
An extensive survey of the "acetophenone", "acetophenone derivatives", and "biological activities" was conducted in scientific databases, including Scopus, Web of Science, PubMed, Google Scholar and Reaxys.The articles which included reports of novel isolated acetophenone were taken into account; however, the synthetic ones were excluded.Also, the reference lists of the included studies were manually investigated.Figure 1 illustrates the number of papers that have reported the isolation of novel acetophenone derivatives from natural resources.The number of isolated novel acetophenone compounds from different families of plants and fungi is also depicted in Fig. 2. 3 Acetophenone derivatives produced by plants

Rutaceae
Containing well over 2040 species categorized within around 170 genera, Rutaceae family, many members of which are aromatic plants [10] is well-known for its rich chemical profile that makes it the most chemically versatile plant family [11].Species of Rutaceae have been used in the industries of gastronomy and perfumery and also in traditional medicine [10].Regarding biological activities, the species of this family have displayed to possess antimicrobial, anticholinesterase, antidiarrheal, antileishmanial, larvicidal, antiprotozoal, fungicidal, and antioxidant activities [10].

The genus Melicope
Consisting of around 250 species, Melicope plants are scattered through the tropical regions of southern hemisphere [12].Like genus Acronychia, the species of genus Melicope have been utilized for their therapeutic and healing properties during centuries [13].The chemical diversity of Melicope species is owed to the presence of compounds such as flavonoids, benzopyrans, alkaloids, and acetophenones [14].Prenylated acetophenone compounds, however, are the key compounds that constitute the chemotaxonomic traits of the genus [15].Li et al. reported the isolation of meliviticine A (1) and meliviticine B (2) from M. viticina (16).The former (1) was identified to be a non-aromatic prenylated isopropylated acetophenone derivative; furthermore, the zero value of the specific optical rotation of 1 hinted to it being a racemic mixture. 2 was also figured to be an isopropylated rearranged prenylated acetophenone [16].The application of subsequent chiral HPLC resolution led to the isolation of the two pairs of enantiomers (1a and 1b) and (2a and 2b) for 1 and 2, respectively [16]. 1 and 2 were moderately effective against six strains of bacteria and fungi [16].Fig. 2 The number of acetophenone compounds isolated from natural sources including plants and fungi [18].Nine more acetophenone derivatives, namely melicolones C-K (14-22) were also isolated from M. pteleifolia and examined for their drug resistance reduction characteristics [19].14-17 were identified to be as racemic mixtures and 18-22 were pure optically upon extraction.18-22 boosted the cytotoxicity of doxorubicin with a reversal fold variating between 6.2 and 13.3 in a mixture with doxorubicin at the concentration of 5 µg/mL [19].[12].Coodeanone B could be detected in the configuration of either E or Z; hence, being counted as two acetophenone derivatives [12].The extract of M. erromangensis revealed to contain six novel acetophenone derivatives (62-67) [33].Acetophenone compounds, refered to by the trivial names of melicopol (68) and methylmelicopo (69) were isolated from the bark of M. broadbentiana [34].Isolated Acetophenones (1-69) from the genus Melicope are depicted in Fig. 3.

The genus Acronychia
The genus Acronychia is comprised of 44 species, distributed mainly along Asia and Australia [35].The various parts of these plants including roots, leaves, stems, and the fruits have a wide range of medical applications such as mitigating diarrhea, asthma, itchy skin, cough, scales, Fig. 3 Acetophenone derivatives reported from Melicope species hemorrhage, fever, etc. [36].Acronychia species are also utilized for the treatment of fungal infection, spasm, pyrexia, stomachache, and rheumatism [35].The species of the genus Acronychia have been a rich source of bioactive compounds including flavonoids, quinoline, lignans, steroids, coumarins, triterpenes, acridone alkaloids, and acetophenones [35].Apart from owning therapeutic characteristics, different part of Acronychia plants have had other usages as their essential oil (EO) is used in cosmetics and their aerial parts are used as food and condiments [35].The chemical compounds of Acronychia oligophlebia were studied by Chen et al. and seven new acetophenone-derived compounds were identified.These compounds, named acrolione A-G (70-76) were all discerned to be responsible for the antioxidant activities of their host plant as they were elucidated to possess the pertaining effects, using DPPH radical-scavenging capacity and FRAP assays.As regards the anti-inflammatory characteristics, 70, 72, 73, and 74 proved to be effective at the IC 50 values of 26.4,46.0, 79.4, and 57.3 µM against RAW 264.7 cells, respectively [37].Three prenylated acetophenone derivatives, called acronyculatin (P-R) (77)(78)(79), were also extracted from A. oligophlebia by Niu et al. [16].The cytotoxic activity of 77-79 against MCF-7 cancer cells was tested, which resulted in the inhibitory effect at the IC 50 values of 56.8, 40.4,and 69.1 µM, respectively [16].Yang et al. did conducted another investigation on A. oligophlebia which resulted in the isolation of six new acetophenone derivatives from the leaves of the plant (80)(81)(82)(83)(84)(85).The cytotoxic activity of 81-85 were evaluated against MCF-7 cancer cells.81 and 85 exhibited moderate inhibitory activities with the IC 50 values of  [38].
Acrovestone (86) was extracted and structurally elucidated from A. pedunculata by Wu et al. [39].This compound displayed potent cytotoxic activity by exerting total inhibition at the concentration of 0.5 µg/mL in human KB tissue culture.It also demonstrated strong cytotoxicity against A-549, L-1210, and P-388 cancer cells at the ED 50 values of 0.98, 2.95, and 3.28 µg/mL, respectively [39].The continuation of examination on A. pedunculata led to the extraction of an undescribed arylketone acetophenone (87) [40].Ito et al. discovered three novel acetophenone compounds, namely acrophenones A-C (88-90), in A. pedunculata, all of which failed to inhibit the growth of five leukemia cell lines (NALM6, Jurkat, HPB-ALL, K562, and PBMNC [41].In pursuit of exploiting the chemical components of A. pedunculata for cancer prevention application, three more acetophenone derivatives were extracted from A. pedunculata by Ito et al., denoted acrophenones D-F (91-93) [42].Kouloura et al. isolated three more acetophenone dimers from A. pedunculata and elucidated them as: acropyrone (94), acropyranol A (95), and acropyranol B (96).It is noteworthy that prenylated acetophenone dimers are found exclusively in the genus Acronychia [43].The continuation of research on A. pedunculata, led to the isolation of five more acetophenone compounds by Su et al. acronyculatins A-E ( 97-101) [44].77 was also discovered to be in the chemical profile of A. pedunculata [45].Upon the application on murine leukemia P-388 cells, 77 displayed an inhibitory effect with the IC 50 value of 15.42 µM [45].Acetophenone compounds, assigned as acroquinolones A-B (102 and 103), belonging to a class of acetophenonealkaloid hybrids were extracted from A. pedunculata (L.) Miq.These compounds were tested against a group of cancer cell lines and proved to exhibit minor inhibitory effects against A549 and HCT116 and moderate cytotoxicity against HT29 and HeLa with the IC 50 values of 21.8 and 14.2 µg/mL, respectively [46].Nathabumroong et al. isolated an isoprenylated acetophenone, named 5'-prenylacrovestone (104) from A. pedunculata [47] (106), respectively, the remainder of isolated compounds exhibited IC 50 values excessing 40 µM for the collective cell lines [48]. A. crassipetala was elucidated to host two prenylated acetophenones, namely crassipetalonol A (112) and crassipetalone A (113).The latter (113) had been previously detected in Euodia lunuankenda, along with the report of its fungicide activity [30], and Urtica dioica L.. 112 also showed to possess high levels of toxicity and little to none antibacterial traits when tested at the high concentration of 156 µM against ESKAPE pathogenes [49]; Comparatively, 113 elucidated to have strong antibacterial activity as it inhibited Entercoccus faecium and Gram-positive bacteria, S. aureus at the MIC 75 values of 2.6 and 20.6 µM, respectively [49].The derived acetophenone compounds from the genus Acronychia are illustrated in Fig. 4.

Asclepiadaceae
The biggest genus of the family is Cynanchum L., the species of which have been used in traditional medicine for the treatment of various diseases and disorders [74].The phytochemical components of those species account for their immune regulation, anti-tumor, and anti-oxidation properties [75].Hwang et al. extracted two acetophenone derivatives, cynandione A (156) and cynanchone A (157), from the roots of Cynanchum wilfordii, neither of which showed any multidrug-resistance [76].In another study on the components of the root bark of C. wilfordii, three acetophenone derivatives, namely cynwilforones A-C (158-160) were discovered by Jiang et al. [77].158 reportedly exhibited hypoglycemic effects in the primary hepatocytes of mice by inhibiting hepatic gluconeogenesis through down-regulating the expression of G6P and PEPCK enzymes, which are responsible for the control of gluconeogenesis [77].The application of two doses of 158 at 20 µM and 40 µM yielded the suppression of hepatic gluconeogenesis by 12.5% and 29.4%, respectively; hence, positing the potential healing traits of the root barks of C. wilfordii, along with their current use for mitigating neurasthenia, abscesses, impotency, and lumbago [77].Cynandione A (156) and its dimers, cynandiones B & C (161 and 162) were isolated from C. taiwanianum [78].In continuation of this study, one more acetophenone derivative was identified and extracted from C. taiwanianum, named cynanchone D (163) [78].Cynanchone A (157) was also isolated in this assay [78].A cytotoxic acetophenone, called cynantetrone (164) was isolated from C. taiwanianum by Huang et al. [79].The assessment for its bioactivity revealed a cytotoxic trait against PLC/PRF/5, and T-24 cancer cell lines with the ED 50 values of 6.6 and 3.5 µg/ mL.The inhibitory effect of 164 on KB cell lines was proven to be insignificant [79].Having investigated C. bungei, Li et al. isolated four acetophenone glucoside compounds which were regarded to as bungeisides A-D (165-168) [80].This species later exhibited to possess four more novel acetophenone compounds identified as 4-hydroxyacetophenone (169), 2,5-dihydroxyacetophenone (170), baishouwubenzophenone (171), and 2,4-dihydroxyacetophenone (172) [81].169 was also later discovered in C. auriculatum and C. wilfordii [82][83][84].Figure 7 shows the structures of extracted acetophenones from Asclepiadaceae.

Myrtaceae
Family Myrtaceae consists of about 142 genera and 5500 species.Myrtaceae is well-defined for its glandular leaves that contain aromatic polyphenolic and terpenoid substances [101,102].The majority of Myrtaceae species are trees that mainly distributed in tropical to temperate regions [102].The EO of Mytraceae plants is primarily consisted of monoterpenes and sesquiterpenes, and often the mixture of both.Complex terpenes, such as triterpenes are also found in less values.Other compounds, like alkyl derivatives, β-triketones and aromatic compounds, such as acetophenone compounds also occur in the species, however, less commonly [102].Eucalyptus gomphocephala is one of the most widely used plants with versatile uses across the globe and it has been used for therapeutic purposes since ancient times for its antiseptics and respiratory tract infection inhibitory features, etc.  [104].Both compounds revealed to be moderately effective against neuraminidase of various strains of swine influenza virus including H9N2, H1N1, H1N1 (WT), and H274Y.197 expressed inhibitory effects at the IC 50 values of 38.00, 45.57, 43.84, and 36.72 µM, respectively, as did 198 at the IC 50 values of 40.33, 48.25, 44.13, and 48.07 µM in the same order [104].The screening of the extract from the cloves of Syzygium aromaticum revealed two previously-unknown acetophenones (199 and 200) [105].Both compounds were subjected for their inhibitory abilities of prolyl endopeptidase, the result of which demonstrated the IC 50 values of 218.9 and 17.2 µM attributed to 199 and 200, respectively.This assay shed light on the potent applicability of 199 for preventing memory loss [105].Ryu et al. also isolated phloroacetophenone-O-glycoside compounds, 2,4,6-trihydroxy-3-methylacetophenone-2-O-β-D-glucoside (201) and 2,4,6-trihydroxyacetophenone-3-C-β-D-glucoside (202) from S. aromaticum; 201 was obtained from the flower buds of the plant [106], and 202 from both flower buds and its leaves [106,107].The cytotoxic activities of 201 and 202 were assessed against A2780 human cancer cells which disproved the pertaining abilities of both compounds as they both showed the inhibitory effect with the IC 50 of > 100 µM [106].These novel acetophenone compounds are shown in Fig. 9.

Other Families
Four acetophenone derivatives (203-206) were extracted from Iris japonica (Iridaceae) by Shi et al. [108].Hoang et al., also, identified apocynin acetophenone (207) from Iris spp [109].Apocynin (207) is an important naturally occurring acetophenone with various pharmacological activities.It has been studied for its potential in treating a variety of disorders, including diabetic complications, neurodegeneration, cardiovascular disorders, lung cancer, hepatocellular cancer, pancreatic cancer, and pheochromocytoma [110][111][112][113].It has been formulated into various nanoparticles to enhance its absorption and duration of action [114].Additionally, apocynin has shown promise in the treatment of various disorders, including diabetic complications, neurodegeneration, cardiovascular disorders, lung cancer, hepatocellular cancer, pancreatic cancer, and pheochromocytoma [112].Its primary reported mechanism of action is as an NADPH oxidase (NOX) inhibitor, but recent studies have also highlighted its off-target effects, such as scavenging non-radical oxidant species [115].Zulfiqar et al. isolated three acetophenone C-glycosides (208-210) from the stem of Upuna borneensis (Dipterocarpaceae) using acetone solvent [116].Lendl [117].A polyoxygenated acetophenone, denoted as 2,6-dimethoxy-4-hydroxyacetophenone (214) was identified in the bulbs of Pancratium maritimum (Amaryllidaceae) [118].Analyzing the constituents of P. biflorum led to the identification of two previously-undiscovered acetophenone glycosides, named 4,6-Dimethoxyacetophenone-2-O-β-Dglucoside (215) and 2,6-Dimethoxyacetophenone-4-O-β -D-glucoside (216) [119].Miyazawa and Kawata detected the presence of two acetophenone compounds, namely paeonol (217) and acetanisole (218), in the essential oil of Cimicifuga simplex (Ranunculaceae) [120].Paeonol (217), a significant bioactive acetophenone, shows a range of pharmacological and biological activities.It has been shown to possess substantial anticancer effects, including the induction of apoptosis, inhibition of cell proliferation, and modulation of multiple signaling pathways [121].Paeonol also shows potential as a therapeutic agent for atherosclerosis, with anti-atherosclerotic effects and protective effects on important cell types involved in the disease [122].In osteoarthritis, paeonol has been found to mitigate inflammation, prevent extracellular matrix degradation, and inhibit chondrocyte apoptosis through the activation of the SIRT1 pathway [123].Paeonol has proven to be effective in treating chronic dermatitis, reducing scratching behavior and skin inflammation [124]; It also has therapeutic effects in ulcerative colitis (UC) [125].It has also shown promise in treating dry skin diseases by reducing inflammation and itching behavior through the CXCR3 pathway [124].Furthermore, paeonol has various applications in different industries.It has been found to effectively inhibit the growth of Aspergillus flavus, a fungus that can damage agricultural products [126].Paeonol treatment can also promote reendothelialization, the process of regrowing the endothelial layer of blood vessels, which is important for the treatment of vascular diseases [127].Sancin (1971) identified acetophenone derivative, named acetovanillone (219) in the roots of Apocynum venetum (Apocynaceae) [128].It also yielded p-hydroxyacetophenone (126) that was hitherto unidentified in the plant [128].Research into Polygonum multiflorum from Polygonaceae family afforded a novel acetophenone compound, called polygoacetophenoside (220) [129].[130].
There are reports of the presence of acetophenone compounds in Gymnosperms.Osswald et al. reported the extraction of p-hydroxyacetophenone (127) in Picea abies (spruce needles) (Pinaceae) and explored the fungitoxic activity of that compound towards Cladosporium cucumerinum and Ospbaera kalkhoffii [145].Attempts to screen the compounds from the members of gymnosperms perpetuated as Inatomi et al. identified seven acetophenone derivatives from Juniperus occidentalis (Cupressaceae).These compounds were elucidated as Juniperoside III -IX (235-241) [146].Figure 10 illustrates the aforementioned acetophenone compounds.

Fig. 11 Fungi-derived acetophenone compounds
A summary of the biological activities of acetophenones are listed in Table 1.

Conclusion
Natural products (NPs) are a diverse and abundant source of biologically active compounds with enormous potential for new drug discovery and other applications.In today's clinical landscape, more than half of all drugs in use are either natural products or their derivatives, with plants contributing no less than a quarter of this total [153].NPs have been used for centuries to treat a wide range of diseases, and modern research has shown that they possess a wide range of biological activities, including cytotoxicity, antibacterial, antifungal, antiviral, and antiparasitic activity.NPs are produced by a variety of organisms, including microbes and plants [154].However, only a small fraction of the world's biodiversity has been studied for its pharmaceutical potential, suggesting that the vast majority of NPs remain to be discovered.Acetophenone compounds which are present in a relatively wide variety of plant species and some strains of fungi are garnering increasing focus by natural products researches as they have proven to possess diverse biological activities.The exploration of various plant and fungal species has yielded 266 natural acetophenone compounds and derivatives, many of which exhibit a wide range of biological activities.This illustrates the depth of possibilities that the study of acetophenones can offer in the realms of medicine and science.

Fig. 1
Fig.1 The number of published papers reporting the isolation of acetophenone derivatives since 1961

Fig. 7
Fig. 7 Acetophenone derivatives reported from the family Asclepiadaceae

Table 1
Biological activities reported from isolated acetophenones in detail